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Monday, July 29, 2013

Long Term Effects of Hormone Therapy on Cognitive Function in Postmenopausal Women


Dear Readers,

A recent article in JAMA Internal Medicine, examined whether estrogen hormone therapy in post-menopausal women, aged 50-55 years, had long term effects on cognitive function. The study included post-menopausal women from the Women’s Health Initiative study, who had begun treatment in the two randomized, placebo-controlled, clinical trials of hormone therapy when they were aged 50-55 years.

A total of 1,326 women, enrolled in the study, and had a mean range follow up of seven years (3.9-10 years). Cognitive function was measured by the telephone administered Telephone Interview for Cognitive Status – modified (TICS-m). The TICS-m assessed a variety of cognitive functions, namely, immediate and delayed verbal memory, attention and executive function, verbal fluency and working memory.

Overall, there was no difference in the mean scores on cognitive tests between women who had been assigned to the active or placebo groups and were consistent between the groups who received conjugated estrogen (CEE) and medroxyprogesterone acetate (MPA). Assignment to the CEE group, demonstrated slightly lower scores on verbal fluency, with CEE + MPA showing slightly better scores. Adherence to medication and overall exposure to medication were weakly correlated with higher executive function but did not have any relation to the size of the treatment effect for any measure of cognitive function.

The findings from this study, suggest that for cognitive function, no overall long term benefit or long term harm was found for women who underwent CEE therapy. These findings add to the literature on women that has found a variety of findings across the spectrum: with verbal fluency improved, harmed or unchanged by hormone therapy. Higher levels of endogenous estrogens have also been associated with greater declines in verbal fluency in older women. So what does this mean? Results from this study suggest no adverse long term effect on cognitive function of prescribing CEE-based medications to younger, post menopausal women.

Here are three articles you can read to learn about this particular study or the latest research on women’s health.

Espeland MA, Shumaker SA, Leng I. et al Long term effects on Cognitive function of Post menopausal Hormone Therapy Prescribed to Women aged 50-55 years. JAMA Intern Med.

Shumaker SA, Legault C, Kuller L., et al. Women’s HealthInitiataive Memory Study Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in Post menopausal women: Women’s Health Initiative Memory Study. JAMA 2004:291 (24): 2947- 2958
Kang JH, Grodstein F. Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiol Aging 2012: 33 (7): 1129 -1137.

Thanks for reading.


Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Co-Leader-Clinical Core, Rush Alzheimer’s Disease Center
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL






















 
Author: Neelum Aggarwal MD at 1:57 PM 0 Comments

Thursday, July 25, 2013

Genetic Data Mining Result: Are There AD Subtypes?


Dear Readers,

As you may recall, patients who are carriers of the APOE4 gene are at higher risk for Alzheimer's disease. In a paper published this week in the journal Nature, researchers report key molecular pathways inside neurons that are altered by the presence of APOE4.

The researchers applied big data mining techniques to genetic data from the Alzheimer’s Disease Neuroimaging Initiative to look for patterns in changes in gene activity in 100 non-demented people who carried APOE4 genes and 100 non-demented people who did not. The team reports changes in the expression of 215 genes between carriers and non-carriers of APOE4. Out of those, they identified 20 that appeared to be "master regulators" of key reactions inside neurons.

Two of those genes, SV2A and RNF219, appear to change how they functioning depending on the person’s apolipoprotein E status. Many of these genes have been implicated by other groups, so this finding is confirmatory of those studies as well.

Apolipoprotein E, or APOE, is a molecule that transports cholesterol out of the brain. There are three major forms of this cholesterol carrier -- APOE2, APOE3 and APOE4. People who make APOE4 are at increased risk for Alzheimer's disease, people who make APOE3 have a neutral or intermediate risk, and people who make APOE2 appear to be at lower risk for developing the disease.

In the presence of APOE4, neurons seem to alter how they process the amyloid precursor protein, which is cleaved to produce beta-amyloid. One implication of this work is that different genetic forms or subtypes of Alzheimer's disease may have specific underlying mechanisms, and therefore respond differently to medications.

More research is needed to confirm these results, but this paper represents a major step in applying genetic research and data mining techniques on existing data sets already available to make new discoveries.

Thanks for reading,

Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 10:04 PM 0 Comments

Thursday, July 18, 2013

"Senior Moments" or an AD Tipping Point? Reviewing the AAIC Subjective Memory Concern Research


Dear Readers,

Five reports presented this past Wednesday at the Alzheimer’s Association International Conference (AAIC) in Boston found healthy people who self-report that their memory is declining, sometimes referred to as ‘senior moments,’ even when cognitively normal on testing, may already have Alzheimer’s-related changes in their brains. These individuals have been found to also more likely to be subsequently diagnosed with cognitive impairment down the road. The key aspect is that there is a sense that one’s memory is declining, rather than an occasional forgotten name or misplaced item.

At a panel presentation on ‘subjective cognitive decline’ researchers from various research groups presented data showing early memory complaints may be the initial signs of progressive cognitive decline years later. ‘Subjective cognitive decline’ is when a person senses that their memory abilities are slipping even before others have noticed.

Researchers from the University of Kentucky reported results from a study of 531 people, average age 73. Those who reported a change in memory function since their last doctor visit were nearly twice as likely to be diagnosed with dementia or mild cognitive impairment about six to nine years later.

In another study of 3,861 nurses who were at least 70 years old, subjects were asked about memory symptoms and periodically tested for them later. About 900 of the subjects carried the ApoE4 gene, which is known to increase the risk for Alzheimer’s dementia. Among the ApoE4 carriers, concern about a single memory symptom predicted future memory decline on tests over the next six years. In the others without the gene, concern about three or more memory symptoms was linked to memory decline on tests.

And, in a study out of Harvard Medical School, researchers found that complaints about memory decline correlated with the amount of beta-amyloid seen on brain scans of 189 people 65 and older. This confirmed an earlier study of 131 subjects that also correlated memory complaints to amyloid plaque burden.
Finally, a study of 2,230 mentally healthy Germans found that those who complained of memory problems at age 80 were much more likely to have such problems at age 88 than those without the complaints.

So, cognitively normal people with some types of memory concerns were more likely to have Alzheimer’s pathology in their brains. As we try to move earlier and earlier in diagnosing AD in its development, ‘subjective cognitive decline’ will likely play an important role in identifying patients before reaching the MCI stage.

Thanks for reading,

Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 5:20 PM 0 Comments

Thursday, July 11, 2013

Draft Medicare Coverage Decision on Amyvid Scans


Dear Readers,

Last week, the Centers for Medicare and Medicaid Services (CMS) issued a draft decision memo saying that it would pay for Amyloid PET scans only if patients were taking part in clinical trials. Instead of agreeing to routinely pay for the $3,000 test, CMS proposed "Coverage with Evidence Development", a designation that suggests there are still gaps in the evidence over the benefits of the test. Using this designation allows the agency to gather more data by paying for scans in patients taking part in clinical trials. Once those are completed, CMS plans to use the data to render a final decision on coverage.

As readers of this blog will recall, last April, the FDA gave final approval of Amyvid, a chemical tracer that allows visualization of beta-amyloid plaques in the brain using a PET scan. Before the development of imaging agents, amyloid plaques could be determined only after death, by examining the brain during an autopsy. Observing no plaques helps rule out Alzheimer’s disease, while the presence of amyloid plaques provides evidence consistent with the disease.

CMS did cite evidence that amyloid scans may be of use to rule out Alzheimer's in certain difficult-to-diagnose cases and to help identify patients who would be good candidates for clinical trials seeking better treatments or prevention strategies for the disease. And last year, the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging sent CMS a report detailing the limited circumstances under which the test would be appropriate. These criteria were published earlier this year in Alzheimer's & Dementia: The Journal of the Alzheimer's Association and the Journal of Nuclear Medicine. According to those criteria, appropriate candidates for amyloid PET imaging are limited to:

1. Those who complain of persistent or progressive unexplained memory problems or confusion and who demonstrate impairments using standard tests of cognition and memory.

2. Individuals meeting tests for possible Alzheimer's, but who are unusual in their clinical presentation.

3. Individuals with progressive dementia and atypically early age of onset (before age 65).

So, where do we go from here? The CMS draft decision is open to public comments for 30 days, and CMS will issue a final decision, likely in October. The final decision will likely remain unchanged, until a disease-modifying treatment becomes available.

As a neurologist actively seeing patients in clinic, I have ordered only a handful of such scans in the past year. All have been for patients who meet one of the criteria above. And the results have been of great value. Not because I was able to change the treatment, but rather, because we were able to at least answer one critically important question, whose answer is life changing: does my loved one have Alzheimer’s disease or not?


Thanks for reading,


By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 10:56 AM 0 Comments

Friday, July 05, 2013

Amylin: An Emerging Theme in AD


Dear Readers,

As many of you may be aware, Type 2 diabetes is a chronic metabolic disorder that increases the risk for dementia, a risk that develops years before the onset of clinically apparent diabetes. Its incidence is far greater among people who are obese. I have discussed the relationship between diabetes, insulin and AD in previous blogs. Essentially, the body becomes resistant to the actions of insulin, and this leads to chronically elevated levels of blood sugar. As the body becomes resistant, more and more insulin is produced, leading to abnormally high levels of insulin in the body, including the brain.

Amylin, also called ‘islet amyloid polypeptide’ is a hormone produced by the pancreas that circulates in the bloodstream along with insulin and plays a critical role in regulating blood sugar levels by slowing the movement of food through the digestive tract, promoting the sense of fullness and preventing spikes in blood sugar levels. In older patients with type 2 diabetes, free-floating amylin forms amyloid-plaques in the pancreas, and is actually a hallmark of type 2 diabetes.

A theme has emerged in the AD field. When over-secreted, certain proteins tend to stick to one another, forming small aggregates, called soluble oligomers, which can be toxic, and over time, deposit into insoluble plaques. These proteins include amylin in type 2 diabetes, prions in Creutzfield-Jacob disease, Lewy bodies in Parkinson’s disease, and more relevant to this discussion, beta-amyloid in Alzheimer’s disease. It has been suggested that it is the toxic oligomers that damage neurons. And they can do so in multiple ways, including inflammation, over-excitation, receptor down-regulation and even activation of latent cell-death mechanisms called apoptosis.

In a recently published paper#, researchers found numerous deposits of amylin in the brain of diabetic patients with dementia. Surprisingly, the researchers also found amylin in the brain tissue of individuals with Alzheimer's who had not been diagnosed with diabetes. They did not find amylin deposits in the brains of the healthy control subjects. The study was conducted using tissue from the brains of 15 patients with both Alzheimer's disease and type 2 diabetes; 14 Alzheimer's disease patients without diabetes; and 13 healthy controls. A series of tests were used to measure how much beta-amyolid and amylin had accumulated in the brain.

What does this finding mean? It may help explain why type 2 diabetics are at much higher risk of getting AD. Additionally, it suggests that other mechanisms may be involved in the brain degeneration observed in AD. For example, about 15 years ago, there was a flurry of papers showing how amylin causes cell death in the pancreas of patients with type 2 DM*. This included an intriguing mechanism that involved amylin opening ‘channels’ in the walls of cells, that led to an influx of calcium into cells and leading to cell death. If the same mechanisms are observed in AD, it may represent another therapeutic target to slow down brain cell death in AD.

#Jackson, et al, Amylin deposition in the brain: A second amyloid in Alzheimer's disease?
Annals of Neurology, July 2013.
*Lorenzo A., Razzaboni B., Weir G. C., Yankner B. A.(1994) Nature 368:756–760; Lin M. C., Mirzabekov T., Kagan B. L.(1997) J. Biol. Chem. 272:44–47
 
Author: Michael Rafii MD, PhD at 3:18 PM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.